title: Design of glycosyltransferase inhibitors: pyridine as a pyrophosphate surrogate.
abstract: A series of ten glycosyltransferase inhibitors has been designed and synthesized by using pyridine as a pyrophosphate surrogate. The series was prepared by conjugation of carbohydrate, pyridine, and nucleoside building blocks by using a combination of glycosylation, the Staudinger-Vilarrasa amide-bond formation, and azide-alkyne click chemistry. The compounds were evaluated as inhibitors of five metal-dependent galactosyltransferases. Crystallographic analyses of three inhibitors complexed in the active site of one of the enzymes confirmed that the pyridine moiety chelates the Mn(2+) ion causing a slight displacement (2 Å) from its original position. The carbohydrate head group occupies a different position than in the natural uridine diphosphate (UDP)-Gal substrate with little interaction with the enzyme.
authors.affiliation: Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2, Glycochimie, UMR 5246, CNRS and Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 6922 Villeurbanne (France), Fax: (+33) 472-448-109.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cuesta-Seijo
authors.forename: Dominique
authors.initials: D
authors.lastname: Lafont
authors.forename: Monica M
authors.initials: MM
authors.lastname: Palcic
authors.forename: Sébastien
authors.initials: S
authors.lastname: Vidal
mesh_terms: D002241:Carbohydrates; D057930:Click Chemistry; D005700:Galactosyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D002241:Carbohydrates; D011725:Pyridines; D005700:Galactosyltransferases; C023666:pyridine
keywords: X-ray diffraction; carbohydrates; click chemistry; inhibitors; ligation